It is known that retinol binding protein 4 (hereinafter sometimes to be abbreviated as “RBP4”) is a sole blood retinol transfer protein mainly produced in the liver.
RBP4 forms a complex by binding to retinol and TTR (transthyretin) and is stably present in blood. When RBP4 is dissociated from TTR and becomes free, it is decomposed in and excreted from the kidney comparatively rapidly. It is unknown whether the binding of RBP4 and retinol is indeed essential for the formation of a complex with TTR. However, fenretinide, a retinol derivative, inhibits binding of RBP4 and retinol, and consequently inhibits formation of a complex with TTR. It is known that administration of fenretinide to an animal induces lowering of blood RBP4 (non-patent document 1).
The relationship between retinol supplied by RBP4 and ophthalmic diseases has been reported. For example, an excessive vitamin A level in the eye can induce various retina diseases including macular degeneration, and a decrease in RBP4 is effective for the prophylaxis or treatment of these ophthalmic diseases (patent document 1).
Fenretinide has been investigated in patients affected with geographic atrophy (GA), which is the most progressed form of atrophic age-related macular degeneration (AMD). Fenretinide has been suggested to discontinue accumulation of retinol (vitamin A) toxin via affinity to RBP4. It is assumed to delay formation and accumulation of toxicity by-products, for example, A2E (bis-retinoid pyridinium) considered to be involved in the loss of eyesight in diseases such as GA and the like. Sirion Therapeutics, Inc. publicly reported affirmative results of the analysis of phase two tests for evaluating fenretinide for the treatment of GA related to AMD.
From the above, application of a medicament having an action to decrease blood RBP4 value (concentration) to the prophylaxis or treatment of ophthalmic diseases is expected. In the present specification, the “action to decrease blood RBP4 value (concentration)” is sometimes referred to as an “RBP4-lowering action”, and the “medicament having an action to decrease blood RBP4 value (concentration)” is sometimes referred to as an “RBP4-lowering drug”.
Patent document 2 discloses the following compound having a RBP4-lowering action, and useful for the prophylaxis or treatment of diabetes, obesity and the like.
wherein each symbol is as defined in the document.
Patent document 3 discloses the following compound having a RBP4-lowering action, and useful for the prophylaxis or treatment of diabetes and the like.
wherein each symbol is as defined in the document.
Patent document 4 discloses the following compound having a RBP4-lowering action, and useful for the prophylaxis or treatment of diabetes, age-related macular degeneration and the like.
wherein each symbol is as defined in the document.